This proposal outlines a study of the fundamental aspects of the cyclization of 1,5-hexadiyne-3-enes to 1,4-dehydrobenzene diradicals, the essential transformation that triggers the double-stranded cleavage of DNA by several recently discovered antibiotics, the esperamicins and calicheamicins. It has been proposed that the DNA cleavage reaction is initiated by binding of the antibiotic into the minor groove of double-helical DNA, followed by a series of reactions that result in cyclization of the 1,5-hexadiyne-3-ene system in the drug to a substituted 1,4-dehydrobenzene diradical intermediate. The radical centers in this intermediate abstract hydrogen from the deoxyribose backbone of the nucleic acid, resulting in cleavage of the biopolymer. Although these results have stimulated research in several laboratories aimed at the synthesis and study of esperamicin and calicheamicin model systems, there, is little work under way directed at studying the fundamental properties of the cyclization or of the 1,4-dehydrobenzene inter-mediates themselves. Questions of this type that will be addressed in the work outlined in this proposal include: (a) the search for a better understanding of the factors that influence the rate and thermodynamics of the 1,5-hexadiyne-3-ene-to-1,4-dehydrobenzene cyclization; (b) the search for a better understanding of the chemistry, structure, thermodynamic properties and spin states of 1,4-dehydrobenzenes; (c) the effect of structural changes on the chemistry of the diradical; (d) the developments of methods to detect and study the intermediate directly; (e) the relationship of the diradical to alternative structures, such as ring-closed and zwitterionic 1,4-dehydrobenzenes; and (f) the potential for using reactions related to the 1,5-hexadiyne-3-ene cyclization to generate other aromatic diradicals analogous to 1,4-dehydrobenzene. The fundamental information sought in this proposal should be directly useful to workers interested in the chemical and biological properties of antibiotics that induce DNA cleavage by aromatic diradical intermediates.